Throwing molecular wrench into gene control machine leads to 'melting away' of leukemia

January 8, 2018, Cold Spring Harbor Laboratory
By inducing the expression of a small peptide in mouse models of human AML, CSHL researchers were able to prevent MYB, a major cancer enabler, from promoting cancer growth. Imaged 9, 11, and 13 days following introduction of the peptide, mice from the experiments show dramatic differences in outcome. In the left two columns, control (far left) and treated mice in which the peptide was not activated move from pervasive cancer (blue bioluminescence) to terminal (red). Some of the mice did not survive 13 days (blank panel). In contrast, the two right columns show control mice (poor outcomes) and treated mice with the peptide activated (far right). In the latter, in the far right column, one sees the cancer melt away, leaving the treated mice nearly cancer-free. Credit: Vakoc Lab, CSHL

Cancer researchers today announced they have developed a way of sidelining one of the most dangerous "bad actors" in leukemia. Their approach depends on throwing a molecular wrench into the gears of an important machine that sets genes into motion, enabling cancer cells to proliferate.

In tests in mice, the newly discovered method has resulted in what the researchers describe as the "melting away" of aggressive blood cancers while at the same time having no harmful impact on the function of normal cells.

The new research by Associate Professor Christopher Vakoc and colleagues at Cold Spring Harbor Laboratory (CSHL) is part of a broader effort in Vakoc's lab to fight the often fatal (AML) by disabling parts of the machinery in cells - called the transcriptional machinery—that determines when genes are switched on and off.

Central players in this machinery are proteins called transcription factors, thousands of which are active in regulating genes across our chromosomes. The question addressed in the new research, published today in Cancer Cell, was how to target one of the most troublesome , called MYB. It's an oncogenic, or -inducing, transcription factor that enables cells to blow through the stop signs that normally prevent out-of-control growth.

Throwing molecular wrench into gene control machine leads to 'melting away' of leukemia
By generating a small protein fragment, or peptide (green square), shaped exactly like the surface where MYB, a cancer promoter, typically binds to a gene co-activator complex (green segment in long rectangle labeled TAF4, above), researchers prevent MYB from activating gene expression and promoting leukemia. Credit: Vakoc Lab, CSHL

"MYB is a dream target in cancer research," says Vakoc, "because it's involved in so many cancers; in leukemia it's special because we know from previous research that by targeting MYB you can get AML not just to stop growing but actually to regress." Deactivating MYB in cancer has been a goal of many research labs..

Yali Xu, a Ph.D. student in the Vakoc lab leading the study, discovered how to selectively take MYB out of the picture in leukemia by throwing a molecular wrench into the mechanism that the transcription factor normally activates. First, the team discovered that MYB activates gene expression by docking at a giant gene-"co-activation" protein called TFIID (pronounced TF-two-D). Next, the they found a tiny weak spot on the massive protein. This Achilles' heel, called TAF12, is a small, nub-like projection. The team then tricked MYB into binding to short protein fragments, or peptides, that are shaped exactly like the place on TAF12 where MYB binds when it is promoting leukemia.

A major achievement in the study was generating this peptide, which acts like a decoy. Experiments in mice that model human AML showed that the peptide finds and binds MYB, preventing it from engaging the TFIID co-activator. This resulted in mouse leukemias shrinking in size by some 80% without causing harm to healthy .

While the peptide is not itself a drug, Vakoc says its action could be replicated by a drug. "It's a concept we're now discussing with the pharmaceutical industry. It is going to take lots of work before it can result in a medicine patients might take. But we're excited about this new approach, because MYB is such an important player in many cancers and until now has eluded efforts to selectively target it."

Explore further: Signaling pathway revealed through which a promising anti-leukemia drug kills cancer cells

More information: Xu, Y et al, "A TFIID-SAGA perturbation that targets MYB and suppresses acute myeloid leukemia." Cancer Cell January 8, 2017.

Related Stories

Signaling pathway revealed through which a promising anti-leukemia drug kills cancer cells

May 14, 2015
Inhibiting a protein called BRD4 critical to the survival of acute myeloid leukemia (AML) cells has shown to be an effective therapeutic strategy. However, the mechanism that explains how the protein works has remained a ...

Scientists discover how leukemia cells exploit 'enhancer' DNA elements to cause lethal disease

November 26, 2013
A team of researchers at Cold Spring Harbor Laboratory (CSHL) has identified a leukemia-specific stretch of DNA called an enhancer element that enables cancerous blood cells to proliferate in Acute Myeloid Leukemia (AML), ...

Researchers identify new strategy for interfering with potent cancer-causing gene

February 11, 2013
Acute myeloid leukemia (AML) is an aggressive blood cancer that is currently incurable in 70% of patients. In a bold effort, CSHL scientists are among those identifying and characterizing the molecular mechanisms responsible ...

Unassuming 'Swiss Army knife'-like protein key to new cancer drug's therapeutic action

November 30, 2015
When preliminary tests show that a new drug has remarkable effectiveness against a lethal illness, everyone wants to know how it works. Often, a mechanism of action is hard to pin down, but when it can be, a candidate drug's ...

Study links mutations in notch gene to role in B cell cancers

October 23, 2017
Notch is one of the most frequently mutated genes in chronic lymphocytic leukemia (CLL), the most common leukemia in adults in the United States. It is also often mutated in other common B cell tumors, such as mantle cell ...

Recommended for you

Resetting the epigenetic balance for cancer therapy

May 22, 2018
Though mutations in a gene called MLL3 are common across many types of cancers, their relationship to the development of the disease has been unclear. Now, a Northwestern Medicine study has identified an epigenetic imbalance ...

Compound in citrus oil could reduce dry mouth in head, neck cancer patients

May 21, 2018
A compound found in citrus oils could help alleviate dry mouth caused by radiation therapy in head and neck cancer patients, according to a new study by researchers at the Stanford University School of Medicine.

Ice cream funds research showing new strategy against thyroid cancer

May 21, 2018
Anaplastic thyroid cancer is almost uniformly fatal, with an average lifespan of about 5 months after diagnosis. And standard treatment for the condition includes 7 weeks of radiation, often along with chemotherapy.

Bladder cancer model could pave the way for better drug efficacy studies

May 21, 2018
Understanding that not all bladder cancers are the same, researchers at the University of North Carolina Lineberger Comprehensive Cancer Center have created a tool that may help them to uncover why only a fraction of patients ...

Breath test breakthrough for early diagnosis of oesophageal and gastric cancer

May 18, 2018
A breath test can successfully detect oesophageal and gastric cancer and could be used as a first-line test for patients, say researchers.

MR spectroscopy imaging reveals effects of targeted treatment of mutant IDH1 gliomas

May 18, 2018
Using a novel imaging method, a Massachusetts General Hospital (MGH) research team is investigating the mechanisms behind a potential targeted treatment for a subtype of the deadly brains tumors called gliomas. In their report ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.